Anthelmintic compositions containing chlorine substituted amides and methods for using same



United States Patent ANTHELMINTIC COMPOSITIONS CONTAINING CHLORINE SUBSTITUTED AMIDES AND METHODS FOR USING SANIE Redginal I. Hewitt, Nanuet, N. Y., and Lincoln H. Taylor, In, Montvale, N. J., assignors to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application June 27, 1956 Serial No. 601,094

Claims. (Cl. 167-53) This invention relates to new compositions of matter and methods of compounding and using the same. More particularly, the invention relates to substituted dichloracetamides in compositions containing a non-toxic edible carrier for elimination of internal parasitic helminths.

The disease 'ankylostomiasis, commonly known as hookworm, is prevalent in warm countries, particularly where plenty of shade and rainfall and a constantly wet soil are present. The four principal species of hookworm are all nematodes of the family Ancyloszomadidae, such as A'ncylostoma ditodenale, Ancylostoma canium, Ancylostoma braziliensis, and Necator americanus. The disease is usually contracted through the skin of the animal and, gaining the capillaries, ascends the bronchial tree and descends the digestive system. The disease is quite prevalent in the southern part of the United States and other countries and is often a public health problem. It thrives particularly where poverty and poorly-balanced diet are prevalent. In the past, it has been treated with compounds such as tetrachlorethylene. This compound, while reasonably eifective, causes nausea and drowsiness. Another compound commonly used is hexylresorcinol. While this, compound is also somewhat efieetive, it isirritating to the mucus membranes and is expensive. Where large-scale treatment of the population is involved, the cost is excessive.

In the past, the treatment of man or animal for parasitic helminths such as hookworms was begun with a 7 fast, followed by dosing with an anthelmintic such as 2-naphthyl thymol, oil of chenopodium, hexylresorcinol, tetrachlorethylene, etc. The toxic anthelmintics along with the hookworms must then be removed from the animals system through the use of purgatives; whereas invention is-the fact that the compounds can be combined with animal feed and given at certain intervals to produce the desired result.

A still further advantage of the compositions of the present invention is the fact that they can be made cheaply from readily available raw material.

We have now found that the highly effective and rela-v tively cheap compositions of the present invention can be made from dichloracetamides having the following structure:

"ice

in which X is a member of the group consisting of Z-naphthyl, 3-quinolyl, phenyl, halophenyl, methylphenyl, cyanophenyl, nitrophenyl, acetylphenyl, dimethylphenyl, methylchlorophenyl, and dichlorophenyl radicals and anon-toxic edible carrier. j

The compounds forming the active ingredient of the compositions are, in general, crystalline solids, sligl1tlyv soluble in most organic solvents and relatively insoluble chloracetamide, N (3 methyl 4 -'chlorophenyl)di-'. chloracetamide, N (4 methyl 3 chlorophenyl) dichloracetamide, N phenyldichloracetamide, N (3 cyanophenyl)dichloracetamide, N (4 bromophenyll dichloracetamide, N (3 iodophenyl)dichloracetamide,

N (3,4 dimethylphenyl) dichloracetamide, N (3 bromophenyl)dichloracetamide, N (4 methylphenyl) dichloracetamide, and the like. The above compounds, in preparing the active compositions, can bev made into tablets, capsules, pills, or other pharmaceutical types of medication by combining them with suitable carriers.

The compositions can also be combined with animal feed and a definite portion of this feed-given at regular inter,-

vals for a short or longer period of time. For example,

in the treatment of hookworm in dogs, it has been found that active compounds of the present invention may be mixed with prepared dog food in the proportions of'approximately one gram per pound and one pound given in divided doses per day for a five-day period is highly efiective.

The following is .the general procedure for testing the present compounds for hookwork activity. Street dogs of various ages and breeds were inoculated per os with with 3000 infective hookworm larvae cultured in conventional charcoal and sand mixtures. Stoll dilution ova counts (pooled samples of feces from a three-day collection) were made three weeks after inoculation with larvae in order to determine quantitatively the degree of parasitemia. Most treatments were started 21 days after inoculation with larvae. Stoll ova counts were made two weeks after treatment, and the dogs were then killed and necropsied. The entire intestine was examined for hookworms, and the number found was recorded, as

indicated in the appended tables. A reduction in the ova counts from 80 to 100 percent in treated dogs was indicative of good activity. An additional criterion of activity was a relatively low number of hookworms in the intestine as compared with non-treated controls hav-- ing comparable ova counts before the treatment period.

The following Table I illustrates the testing results of the compounds of the present invention in .hookworm infections in dogs.

Table II shows :the resultsof: ad;v ministering to dogs N-(beta-naphthyl)dichloraeetamide N 0. Hook worms Found at Necropsy After No. of ova per gram of feces Before Treatment Treatment TABLE III Daily 1 Dose, mg.lkg.

1 In divided doses, twice daily, in the feed.

The compounds of thepresent invention are eifective in from 0.01 g. to 10 g. in the compositions described herein. When used as an ingredient of animal food, it is desirable that it be fed at the rate of 1 to 200 mg. per kg. of body weight per day.

The following examples show the preparation of the active compounds used in the compositions of the present invention.

EXAMPLE 1.-N-(B-NAPHTHYL)-DICHLORACETAMIDE A mixture of g. of B-naphthylamine, 200 ml. of

Yield of EXAMPLE 2.N- (m-CHLORO -DICHLOBACETAN1LIDE To a solution of 16.1 g. of rn-chloraniline in 138 ml.

chloroform, 22.2 g. of sodium carbonate, and 220 ml. of water is stirred at room temperature, dissolving some of the solid. The mixture is cooled in an ice bath to 5 C., and to it is added dropwise a solution of 22.2 g. of dichloracetylchloride in 50 ml. of chloroform over a period of 20 minutes at such a rate that the temperature is maintained at 6-8 C. During the addition a solid precipitates. The reaction mixture is stirred for an additional 30 minutes. To the reaction mixture there is added 200 ml. of heptane and the product is collected on the filter; being washed several times with water. white crystals, 29.2 g. (82%); melting point 162- of chloroform is added a solution of 20 g. of anhydrous sodium carbonate in 200 ml. of water. To this is added dropwise over a period of 15 minutes a solution of 20 g.

3 dosages. Table III summarizes results obta' ed TABLE I few hookworm ova,

TABLE II Dose, mgJkg.

.SJMW 2636 0210 n w 0 HWO FN n 0000 00 0 00 0000 g in own amm a t a r 1 a new V9 0 0 000 0000 000 0000 1 e mo mm mama mama mmmm mwmm m mam we on em new 5 I 0000 0000 000 0000 m m mmwm mama doom name 05 o mm 5 m 2222 3333 4 444 5555 awn N m W 2222 2222 2222 2222 e OSD me P ammo ammo mama mama Many hookworm ova,

Efiects of N-(B-naphthyl) -dichloracetamide against experimental hookworm infections in dogs when administered orally in total doses of from 200 to 500 mg. per kg.

in varying when N-(beta-naphthyl)dichloracetamide is administered by combining in dog food.

Comparison of the effects of substituted dichloracetamides and dichloracetanilides against hookworm infections in dogs when administered at 50 mg. per kg. orally twice daily for five days 0 5 0 g 2 2 4- 5 m S m 00212 03851 5811190000 40 m IOH G m wes km D. .0 do 000mm N WO :N n n m 000000000000000000000000 000a 00B 000 a m m a mm aa+ wan m mum 2 LL 8 T W am i 000000000000 0 000 0 wh 000000000000 0 000 Own 746256497423366 880 f e y i y 1 I i l i 1 1 i y i i i i i 1 i 1 1 i 1 1 mmfim 421521 5%33 42 43 1741 82 N i l ti l i r t r .1 i. Q o a w u m m m a a M 0 0 a m 1 l l r r a r r l l 1 d h h h 0 e 0 0 t 0 0 h h h t 0 C 0 .l d .l 6 1 G 0 0 8 m i i i h i h h c m h i .1 i c d d H m H C .m a w 0 d d d 8 m n r a m m d m a a h m m h 1 a t m e o D a m 0 v. m a w a a c a 0 m 0 v. d o h a i a s 1 .1 1 ya 0 r. t m a C t 0 4 a 0 a a d a 1 I n e I f n w 18 .6 I w 0 B n 08 D mw 0 hd 1d O i m5 0 0 Ad 0 e w m on m a n mm mm a a u m m a T. t l h 1 O .1 0 h. 4 a m a a Wm ma mm .1 Wu 0. d. mm. mmmam m m. N m w a M D cm H Tina M a a a m e t .0 .0 Cu o t Hfl .C.0.0. d M Na Na a no a ue e h 6 Me NaNa Na Ne H i htll bi wl mi iwwi i if} l ns] a n n u u u u u u u u n u n n n N g 2 9 5 3W5 9 7 nm4 0 4 6 3 7 3 31 23 6 m 33 Q 99% .MIMQWM fiunmm XX X XXC XXXXXX XXX Dog No.

=Nun1ber of hookworms approximated by salt flotation.

any hookworm ova.

of-dichloracetyl chloride in 50 ml. of chloroform. The solution is stirred an additional -30 minutes; then- 200 ml. of heptane is :added. The product isfiltered-"oif as white crystals, melting point 107-108 C., weighing 18.8 g;(62%). g EXAMPLE a-ammnyn g-rnrcnnoancnmurnmn Prepared as in Example 2 from dichloracetyl chloride and 4-chloro-3-methylaniline in 81% yield; melting point 146-148 C. after recrystallization from aqueous alcohol.

EXAMPLE 4.4-METHYL.-3,a,a-TRICHLORACETANILIDE" From 17.8 g. of'3-chloro-4-methylai1'iline', 200ml. of chloroform, 20 g. of sodium carbonate, and200 ml. of water; according to the procedure outlined above, there is obtained 26 g. (82%) of product? melting point 134- -135 C., as while crystals. Recrystallization from ethanol afiords white crystals; melting point 135 -136 C.

.' EXAMPLE s DIcHLoRAcETAmmDu e To a solution of 20g. of sodium bicarbonate in200 ml. of water is added 11.5 ml. (11.7 g., 0.126 mole) of aniline. The mixture is stirred and cooled in an ice bath while there is being added dropwise a solution of 13.2 ml. (0.136 mole) of dichloracetyl chloride in 25 3 o h qwi m .Q er a, Pe o o 2 m u s T mixture is stirred at room temperature for an additional hour, and the layers arerthen separated. The aqueous ayer wa h dwi .1 o eh rofmm. and c bined chloroform layers are washed with-50 ml. of water. ,The chloroform solution isdried over magne siumsulfate, filtered and freedfrom almost all the solvent at reduced pressure. Heptane (200 ml.) isadded to the syrup to induce crystallization. The solidiscollected, washed with pentane, and allowed to dryinair. There is .obtained..22.9 g. (89%); melting point Inf-1151C. with sinteringandsublimation above 98,: C. (Lit. melting point 117 0.). The compound is soluble in .ethyl acetate and chloroform. It isnot soluble in water or hexane. r h I c i-EXAMPLE s.- m-cYANo aga-nrcnnonhcnmuinmn This is prepared as in Example 5, fai1d' from14.9 g. (0.126mole)*of'Irn-aminobenzonitrile there is obtained 24.1" g. (8.3%) of m-cyano-a,d-dichloracetanilide with melting" point of "135' 136 C. I Several. recrystalliza tions from benzene-heptane (5:2) give'material. of analytical -purity with a melting point-of 139441 The compound is soluble in chloroform, ethyl acetate, and 'benienej'b'ut is'insoluble in water or. 'pentane.

EXAMPLE 7.-4-BROMO a,a-DICHLORACETANILIDE From .f2li6 ig'fi for?p liromoanilinei -Em mli ofchloroform, 20 g. of sodium carbonate, and 200 ml. of water to which is added a solution of 13.2 mhpf dichloracetyl chloride and 25ml. "of "chloroform, according to the procedure outlined above, there. is" obtained 31 g. (87%) of, while crystalline producg melting point- ,l4 5;--r14.7 C." Rciystalli z'ation from ethanol "afiforr'l's lwiiite crystals; melting point l46l47 C. i i

EXAMPLE s. 3-IODODIcHLORACETANILIDE,

In 140 ml. of water there is dissolved 14.0 g. of sodium carbonate, and to this is added 20.0 g. of niodoaniline in 140 ml. of chloroform. The mixture is cooled to 5 C., and with stirring there is added dropwise 9.2 ml. of dichloracetylchloride in 25 ml. of chloroform over a period of 20 minutes. The stirring is con tinued for /2 hour longer, and the white solid which separates is collected by filtration; 7.3 g., melting point 110-l12 C. The chloroform filtrate is dried over magnesium sulfate and evaporated to dryness at reduced pressure, leaving an oil which crystallizes in the addition of 100 ml. of petroleum-ether (90-100 C.), 8.1 g., melting point 107 -l09 C. The product is the same as obtained in fraction obtained previously. A sample on recrystallizationfor analysis from petroleum-ether (90-1'00 C.) gave a melting' point of'1.10-'112 C. 1' EXAMPLE 9.-N-(3,4-D1METHYL)DICH new.

' ANILIDE 19.9 g. of 3,4-dimethylaniline is dissolved in 190 ml. of chloroform and added to a solution of 26 g. of sodium carbonate in 260 ml. of water. The mixture is stirred and cooledto. 5 C., and 20 'g. of dichloracetylchloride in '50 ml.'of chloroform ,is added dropwise over 20 minutes. After /2' hour of stirring the white needle-like solid which separates is collected by filtration and water washed; yield" 25.5 g., melting point 160-162 0. Recrystallization. from ethanol gives the same melting point.

EXAMPLE 10 .-N-(mBROMOPHENYL)DIOHLORACET- From 21.8 g. 'of m-bromoaniline, 140ml. of chloroform, 20 g. of sodiumcarbonate, and 200 ml. of water according tothe procedure described above, thereis ob-' tained 28.1 g; (79%) of white crystalline product; melt+ in'g'point'10L-103? C. Recrystallization'fl'om h'eptane gives ameltingpdinrof102-103 Cl I EXAMPLE :1' 1. 4-METHYL-a, a-DICHLO'RAOETANILIDE From 13.5 g. of p-toluidine, 200 ml. of; ch1oroform, 20, g, of ,sodium;carbonate,.and 200 ml. of water according-to.the procedure described @above is obtained. 24.1 g. (88%) of white crystalline product;?-melting point l52-l53 C.

EXAMPLE 12.-N-(3-QUINOLYL)DICHLORACETAMIDE SULFATE To a solution of 20.0 g. of 3-aminoquinoline in 262 cc. .of chloroform-was added a solution of22 g. of -an-' hydrous-sodium carbonate in "385 cc. ofwate'r. The mixture was stirred at 5 C. in an ice-bath, and a solution of 22 g. of dichloracetyl chloride in cc.'of chloroform was added dropwise over a period of twenty minutes. The mixture was stirred an additional hour.

Theproduct was collected and washed withwater and heptane The yield is 28.5 g. (82%) of N-(3-quinolyl)- dichloracetamide as white 1 crystals, melting point 116-181 C. dec.

EXAMPLE 13.N- (m-NITRO )DICHLORACETANILIDE To a solution of 17.4 g. of m-nitroaniline in 138 cc. of chloroform was added a solution of 20 g. ofanhydrous sodium carbonate in 200 cc'. of .wate'rf The solutionwas' cooled to 5 C., and a solution of 20 g."ofdi'- chloracetyl chloride in 50 cc. of chloroforni'was added dropwise with stirring over a period of twenty minutes.

The 'solutionwa's stirred an additional thirty minutes and 'the pi'oduct was filtered to yield 19.2 g. offbrown crystals, melting point 102", C. A second crop of ma terial weighing 8.0 g., melting'point l04 C.,"'w'as"obtained from the chloroformlayer of the filtrate by the addition of heptane. Thefirst crop of material was recrystallized from chloroform by the addition of heptane to yield 17.5 g., melting point 104 C. Total yield, 24.5v g.(78%),rneltihgpbiiit1048C I I j can: wmmcrm 'To a solution of 20 g. of sodium carbonate in 200 cc. of water was added 17 g. of 3-aminoacetophenone and 200 cc. of chloroform, and the mixture was brought to +4 C. with stirring and external cooling. A solution of 13.2 cc. of dichloroacetyl chloride in 25 cc. chloroform was added dropwise at a rate which kept the internal temperature between 3 and 7 C. This took 40 minutes. After completion of addition, stirring at room temperature was continued for one hour. The two phases were then separated, and the aqueous phase was washed with 50 cc. of chloroform. The combined chloroform solution was mixed with 200 cc. of heptane, and the solid material which precipitated was filtered oil. The filtrate was evaporated to a small volume, and the solid which formed was collected and added to the {EXAMPLE 15.--2,4,a,ct-TETRACHLORACETANILIDE To a stirred solution of 20 g. of anhydrous sodium carbonate, 200 cc. of water, 20.4 g. of 2,4dichloroaniline, and 200 cc. of chloroform, cooled to C. in an ice bath was added drop-wise a solution of 13.2 cc. of dichlorocetyl chloride in 25 cc. of chloroform. The addition took approximately minutes; the temperature being maintained at between 5 and 7 C. At the end of the addition, a solid separated. Stirring was continued for an additional 30 minutes. After the addition of 200 cc. of heptane, the solid was collected on the filter and washed with heptane to give 28.2 g. (82%); melting point 129-130 C.

We claim:

1. An article of manufacture for veterinary use comprising a quantity of from about 0.01 g. to 10 g. of a compound having the formula:

in which X is a member of the group consisting of.2- naphthyl, 3-quinolyl, phenyl, halophenyl, dihalophenyl lower alkylphenyl, lower-alkylhalophenyl, diloweralkylphenyl, nitrophenyl, acetylphenyl, and cyanophenyl radicals and a non-toxic edible substantially digestible carrier.

2. An article of manufacture for veterinary use comprising a quantity of from about 0.01 g. to 10 g. of a compound having the formula:

01 in which X is a member of the group consisting of 2- naphthyl, 3-quinolyl, phenyl, halophenyl, dihalophenyl, lower alkylphenyl, loweralkylhalophenyl, diloweralkyl- 8 I phenyl, nitrophenyl, acetylphcnyl, and eyanophenyl radials in a pharmaceutical apsule.

4., A method of eliminating helminths from the alimentary canal of domestic animals comprising feeding a quantity sufficient to provide a daily dose within the range of from 1 to 200 mg. per kg. of body weight per day of a compound having the formula El) H/Cl XNHCO in which X is a member of the group consisting of '2- naphthyl, 3-quinolyl, phenyl, halophenyl, dihalophenyl, lower alkylphenyl, lower-alkylhalophenyl, diloweralkylphenyl, nitrophenyl, acetylphenyl, and cyanophenyl radicals and an animal feed.

5. A method of substantially eliminating hookworm from dogs which comprises feeding a quantity suflicient to provide a daily dose within the range of from 1 to 200 mg. per kg. of body weight per day of a compound having the formula:

in which X is a member of the group consisting of 2- naphthyl, S-quinolyl, phenyl, halophenyl, dihalophenyl, lower alkylphenyl, lower-alkylhalophenyl, diloweralkylphenyl, nitrophenyl, acetylphenyl, and cyanophenyl radicals and a dog feed.

6. A composition of matter for veterinary use comprising a quantity of from about 0.01 g. to 10 g. of

'N-(fl-naphthyl)dichloracetamide and a non-toxic edible substantially digestible carrier.

7. A composition of matter for veterinary use comprising a quantity of from about 0.01 g. to g. of N-(m-chloro)dichloracetanilide and a non-toxic edible substantially digestible carrier.

8. A composition of matter for veterinary use comprising a quantity of from about 0.01 g. to 100 g. of 3-methyl-4,a,a-trichloracetanilide and a non-toxic edible substantially digestible carrier.

9. A composition of matter for veterinary use comprising a quantity of from about 0.01 g. to 100 g. of u,a-dichloracetanilide and a non-toxic edible substantially digestible carrier.

10. A composition .of matter for veterinary use comprising a quantity of from about 0.01 g. to 100 g. of N-(3-quinolyl)-dichloracetamide and a non-toxic edible substantially digestible carrier.

Clark: Abst, vol. 49, February 1955, pp. l'611-F and 1614-3. 

1. AN ARTICLE OF MANUFACTURE FOR VETERINARY USE COMPRISING A QUANTITY OF FROM ABOUT 0.01 G. TO 10 G. OF A COMPOUND HAVING THE FORMULA: 